Name: OAS1 immunodeficiency | Acronym: IMD100
Alt. names: Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia | Infantile-onset pulmonary alveolar proteinosis-hypogammaglobulinemia

Gene: OAS1 | MOI: Autosomal dominant | Mechanism of action: Gain of Function

No. of cases in DB: 10 | First reported in: 2018

Last updated on: 2023-03-30 04:46:38 by Xiao P. Peng

OMIM: 618042

Orphanet: 572428

MONDO: 0020840

DOID: -

ClinGen:

Ten patients from eight unrelated families of varying ethnicities have now been identified with de novo heterozygous missense OAS1 gain-of-function (GOF) variants (PMID: 29455859, 34145065). All patients presented with early-onset diffuse lung disease and pulmonary alveolar proteinosis (PAP), characterized by accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure, often accompanied by recurrent viral infections, fevers, dermatitis with mononuclear inflammation, splenomegaly, and inflammatory bowel disease (IBD). Immunophenotyping was notable for hypogammaglobulinemia despite grossly normal peripheral blood T and B cell counts at baseline. However, patients showed low levels of monocytes and B cells during acute flares, along with experimental evidence of increased spontaneous and type I interferon-induced, RNase L-dependent monocyte/macrophage and B cell apoptosis and dysfunction. Patient CD14+ monocytes showed reduced GM-CSF-receptor-expression and STAT5 phosphorylation after GM-CSF- and IL-3-stimulation, whilst both patient-derived alveolar macrophages and iPSC-derived macrophages showed RNase L-dependent defects in cell adhesion and clustering, scavenger receptor expression, and phagocytosis.

Exogenous IgG administration appeared to ameliorate respiratory symptoms and reduce systemic inflammatory responses in at least 3 patients and has been used in nearly all (PMID: 29455859, 34145065), while RNase L inhibition by curcumin was also shown to help modulate the clinical phenotype (PMID: 34145065). Hematopoietic stem cell transplant (HSCT) has now been reported for at least six patients, with clinical disease corrected in two. Of the latter, one was alive and well 2.5 years post-HSCT, while another (who required a second HSCT after graft failure) continued to suffer from EBV reactivation treated with rituximab and immunoglobulin replacement, as well as ongoing diarrhea (PMID: 34145065). One patient in the initially described cohort died of respiratory failure before bone marrow engraftment, whilst another showed respiratory improvement after myeloid engraftment but succumbed to renal failure with pathology evidence of focal glomerulosclerosis (PMID: 29455859). Another patient succumbed at 9 months post-HSCT due to sepsis related to ongoing severe graft-versus-host disease (GvHD) and immunosuppression, while another died of chronic GvHD 3 years after haploidentical HSCT (PMID: 34145065).